Genetic Testing
Today, there are hundreds of different genetic tests, some of them for relatively common disorders, such as cystic fibrosis, and some for very rare diseases. A genetic test is fundamentally different from other kinds of diagnostic tests you might take. Indeed, a whole new field, genetic counseling, has grown up around the need to help patients understand the testing process.
The purposes of genetic tests vary. Some tests are used to confirm a preliminary diagnosis based on symptoms. But other genetic tests measure your risk of developing a disease, even if you are healthy now (presymptomatic testing), or whether you and your partner are at risk of having a child with a genetic disorder (carrier screening).
As the name suggests, a genetic test looks at your genes, which consist of DNA (deoxyribonucleic acid). Each gene contains a chemical message to produce a protein, which has a specific function in the body. Proteins are essential to life-they serve as building blocks for cells and tissues; they produce energy and act as messengers to make your body function. In addition to studying genes, genetic testing in a broader sense includes biochemical tests for the presence or absence of key proteins that signal aberrant gene function.
Some tests look at chromosomes for abnormalities such as an extra chromosome, or an incomplete or missing chromosome. Sometimes, pieces of chromosomes become switched, or transposed, so that a gene ends up in a location where it is permanently and inappropriately turned on or off. Chromosomes are made up of DNA with long chains of genes mixed with inactive DNA. Each of us has 46 chromosomes in the nucleus of each cell, half contributed by each parent. The genes on the chromosomes are responsible for directing our biological development and the activity of about 100 trillion cells in our bodies.
If something goes wrong with an essential protein, the consequences can be severe. For example, a protein called alpha-1 antitrypsin (AAT) clears the lungs of a caustic agent called neutrophil elastase. Those who cannot manufacture AAT because of a defect in the gene that produces the protein often develop emphysema and other complications.
Most genetic conditions come in the form of a mutation in a gene that alters the instructions for making the proteins. These mutations can lead to diseases ranging from those we think of as "genetic diseases," such as cystic fibrosis or AAT deficiency, to those we think of as degenerative diseases, such as cancer and heart disease. In the case of diseases like cancer, heart disease, asthma or diabetes, a combination of factors-some genetic, some related to environmental or lifestyle factors-may work together to trigger the disease.
It's possible to have a mutation, even one for a severe disease, such as cystic fibrosis (CF) and never even know it. That's because genes come in pairs-one contributed by your mother, one from your father. If you have a single such mutation, you are a healthy carrier of the disorder. Such disorders are called autosomal recessive. The unaltered gene in the pair retains the function. The disease becomes a possibility only if two carriers of the same recessive gene have a child. Each child of two carriers of the same disorder has a 25 percent chance of inheriting the disease. It is equally likely (a 25 percent chance) that both parents will contribute their unaltered genes, only the mutated genes, thus there is a 50 percent chance that the child will receive one functioning gene and one mutated gene-in other words, a 50 percent chance that the child will be a healthy carrier like the parents.
Some disorders, such as Huntington disease, are autosomal dominant. If a person has one mutated gene, its effects will cause the disease, even if the matching gene is normal. Thus, each child of a parent with Huntington disease has a 50 percent chance of inheriting the disease. Osteogenesis imperfecta, which causes brittle bones, is another example of a dominant disorder.
Autosomal means the gene is not found on one of the two sex chromosomes, X and Y. If each parent contributes an X chromosome, the child is a girl; an X and a Y chromosome makes the child a boy. Because girls have two copies of every sex-linked gene, they are less likely to have symptoms from X-linked genetic diseases than boys, who don't have a backup copy if an X-chromosome gene is mutated. Examples of X-linked diseases include forms of hemophilia and fragile X syndrome (the most common inherited cause of mental impairment).
Sometimes a genetic defect simply increases risk of developing a disease, often in conjunction with other genetic or environmental factors. For example, a mutation in a BRCA gene increases your risk of breast or ovarian cancer, but only if the companion unmutated copy of the gene in the same cell also acquires a mutation.
A normal copy of BRCA in a breast cell might acquire a mutation due to exposure to, say, an environmental toxin or radiation, or it might become mutated through a sporadic "mistake" during cell division and DNA replication. For a woman without a mutation, it would take two such events in one cell to trigger a BRCA-related breast cancer; for the woman who inherits a BRCA mutation, it takes only one. Other genes can also play a role. A woman with a BRCA mutation who also has a p53 (tumor suppressor gene) mutation would also be more vulnerable, and no doubt there are other genes whose malfunctioning in combination with a BRCA mutation can trigger breast cancer.
There also are other risk factors for breast cancer, such as high alcohol intake (more than two drinks per day), being overweight, not having children or having an early onset of menses.
Most women who develop breast cancer have no known risks for developing the disease other than being a woman or, in the case of an older woman, age. Age is a risk factor for developing many types of cancer.
An increased risk does not necessarily mean you have a disease or will develop it. Genetic test results can yield information to help you and your health care professionals better manage your health, or, in the case of prenatal testing, your baby's care.
Unfortunately, though, genetic tests do not always provide the clear answers you may want. Sometimes a mutation is found that is of uncertain significance. Also, many tests are designed to look for the most common disease-causing mutations. If you or your family has a unique mutation, these tests won't pick it up. Hence, many of the tests boast detection rates of 95 percent or more, but they are not perfect. If you have a strong family history of a disease and uncertain or negative test results, it may be better to play it safe and take added prevention measures as if you had tested positive for the mutation. A genetic counselor can provide guidance.
The Cost of Genetic Testing
The cost of a genetic test varies dramatically, ranging from about $50 to upwards of $2,000. The difference stems largely from the variation in labor intensity of different tests. Some tests look for a limited number of mutations (sometimes only one) known to cause a disease; others require sequencing of the entire gene. It's the difference between looking at a few particular frames of a film for defects and examining the entire reel.
The explosion of genetic research now taking place is expected to bring prices down and dramatically increase the number of tests available. In the coming years, tests may be available to predict your genetic risk of developing heart disease or diabetes, for example, and will help you and your health care professional develop specific strategies for prevention. Preventive efforts can include changing your lifestyle or perhaps taking certain medications, which may be tailored to your specific genetic profile, and early screening to head off the worst complications should you develop the disease.
What is Genetic Counseling?
Because the nature of genetic testing is so complex, with implications for both the person being tested and his or her family, counseling is desirable before taking any genetic test and essential if results come back positive or uncertain. Unlike most medical appointments, a counseling session may be a family affair, with participation of all concerned relatives. Counselors say sometimes a dozen or more relatives attend.
A genetic counselor is a health care professional who is an expert in counseling, genetics and genetic testing. She (most today are women) reviews your family history to determine if there appears to be a hereditary pattern of disease and who might be affected. A genetic counseling session usually lasts at least an hour and includes:
-
gathering background information on your family and the disease under discussion
-
providing information on inheritance, the genetic testing procedure, the possible results and what they mean
Testing usually is not performed at the first counseling session, and there is never any pressure to take a test. Genetic counseling will educate you so you can make an informed decision. If you are feeling ambivalent, counseling won't push you in one direction or the other, but it can help you decide whether testing is right for you.
Because family history is so crucial to deciding whether testing has a chance of identifying a disease-linked mutation, a counselor may request medical records to confirm a diagnosis, especially if you're trying to determine whether a family pattern of cancer is hereditary.
Family member recollections can be inaccurate-who had which disease or even what type of disease. Many conditions either were not discussed or not diagnosed in past decades. A genetic counselor will listen to a family account and help tease out details to better identify potential patterns.
Many women never think about genetic testing until they are considering having a child or have become pregnant. Prenatal testing offers an opportunity to test for chromosomal and common genetic disorders, as well as genetic conditions that have surfaced on either side of the family or for which either parent is a carrier. Counselors recommend a preconception session to discuss carrier testing and prenatal testing options.
Privacy Concerns
Genetic counselors are committed to protecting your privacy. They will not contact other family members without your permission, though they may encourage you to share results that might affect your relatives. Many counseling centers will store records of test results separate from your main medical record to help keep the information out of the hands of insurers and employers, unless you give permission to share. (Of course, if you use insurance to pay for testing, the company will have access to your file.) If you are concerned about your privacy, ask your genetic counselor about the center's policy. Thus far, experts say, there has been little evidence of insurer or employer discrimination based on genetic testing, but that may change once such testing becomes commonplace.
How to Find a Counselor
You can find a genetic counselor at http://www.nsgc.org, the Web site for the National Society of Genetic Counselors. The core credentials are a master's degree in the field and certification conferring the designation of certified genetic counselor (CGC).
Genetic Testing And Children
Up to age 18, genetic tests are used only for diagnosing conditions for which the proper care during childhood or adolescence can make a difference, not for doing carrier screening or testing for diseases that may affect children later in life (presymptomatic testing).
Newborn screening programs are now widely available for genetic diseases treatable early in life. Such a test can indicate elevated risk of a disorder, and a positive result should be followed up with further diagnostics. Below are the most commonly administered newborn screening tests, though remember that not every state administers every test (check with a health care professional to find out):
Phenylketonuria (PKU) is characterized by an inability to metabolize an amino acid called phenylalanine and causes mental retardation unless a specialized phenylalanine-free diet is put in place. Aspartame (Equal) should be avoided if you have PKU.
-
Hypothyroidism can interfere with growth and mental development if not treated.
-
Galactosemia can cause mental retardation if not treated with a diet free of a sugar called galactose, which is found in dairy products.
-
Sickle cell disease makes a baby more susceptible to infection but early treatment with penicillin reduces the risk.
Newborn screening programs designed to test for 30 conditions are now being introduced in some hospitals. If this type of program is not available at your hospital, you can obtain your own kit by mail and have your baby tested at the hospital or your pediatrician's office.
Prenatal Testing
Prenatal testing to detect chromosomal defects and inherited genetic disorders has been widely available for women with high-risk pregnancies since the 1970s. These days nearly every pregnant woman in the U.S. has a preliminary maternal serum screening test performed.
The serum test, a simple blood test, is usually performed between week 15 and week 18 of the pregnancy (as measured from the start of the most recent menstrual period). The test evaluates your risk of having a baby with:
-
An open neural tube defect. When the neural tube fails to close, the baby is born with an opening in the head (anencephaly) or spinal cord (spina bifida). Babies with anencephaly are stillborn or die soon after birth; those with spina bifida need surgery and may be paralyzed.
-
Down syndrome (also called Trisomy 21). An extra copy of chromosome 21 causes Down syndrome, characterized by mental retardation, certain facial features and sometimes heart defects.
-
Trisomy 18. An extra copy of chromosome 18 causes this syndrome, which usually proves fatal during the first year of the baby's life and is associated with severe mental retardation.
The blood screen does not look directly at genetic material but instead measures three substances-alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin-to determine whether you are at increased risk of having a baby with one of these disorders. A key fact to remember is that this test does not diagnose the disorders-it only screens for the substances. Further testing is always suggested to make a diagnosis.
Indeed, most of the time, the fetus is not affected with the disorder even if the screening result is abnormal. According to Genzyme Genetics, a genetics laboratory based in Framingham, Mass, out of 1,000 serum screening tests, 25 will suggest an increased risk for open neural tube defects, but only one or two of the fetuses will have such a defect. Likewise 70 out of 1,000 will test positive for increased risk of Down syndrome, but only one or two fetuses will actually have the condition.
Most labs offer the standard "triple marker" serum screening test, which picks up about 70 percent of Down syndrome cases among women under 35, and 85 to 90 percent in women 35 and older. A recently introduced four-marker test incorporating a measure for a chemical called inhibin-A improves detection rates for Down syndrome by five to 10 percentage points. Some centers also offer first trimester screening to determine if a woman is at increased risk for having a baby with Down syndrome or trisomy 18. The test has two parts and both should both be performed between the 10th and 13 weeks of gestation. One part tests levels of maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in the mother's blood. The other measures the nuchal thickening (measure of fetal neck thickness) through a specialized ultrasound. This test detects more than 90 percent of fetuses with Down syndrome and approximately 97 percent with Trisomy 18. However, it is a
screening test and still requires a confirmatory chorionic villous sampling or amniocentesis to make the definite diagnosis.
A screening test does not diagnose a problem. It should not be used to make either treatment decisions or decisions to terminate a pregnancy, but rather should be used to determine appropriate next steps.
Diagnostic Follow-Up In Prenatal Testing
If a screening test indicates a higher-than-average risk, your health care professional may want to perform a basic ultrasound, which can help determine the gestational age of the fetus and show if a woman is carrying twins. If either of these factors accounts for the abnormal triple screen test result, no further testing is needed. Otherwise, a more detailed ultrasound examination may be performed, which allows a look at the baby's brain and spinal cord, as well as other parts of the body. This ultrasound can often identify an open neural tube defect or other malformation associated with an abnormal screening test.
Your health care provider may suggest you consider either amniocentesis or chorionic villus sampling (CVS). Both are diagnostic tests to determine whether the fetus actually has the disorder in question. Amniocentesis is performed more frequently and should be the choice if you're at risk having a child with neural tube defects.
If you have amniocentesis, a doctor will use a needle to withdraw a sample of amniotic fluid (the fluid surrounding the fetus) for analysis. The procedure is typically performed during the second trimester, at 15 to 18 weeks.
Amniocentesis or CVS are also offered for high-risk pregnancies, which could be indicated by any of the following:
-
you will be 35 or older at delivery
-
your family has a known genetic disorder
-
you have had a previous child with a birth defect
-
you and your partner are carriers of the same recessive disorder
Both CVS and amniocentesis can cause cramping, and a small number of women have miscarriages following the procedures (the risk is higher with CVS, but still only about one percent).
CVS is an alternative to amniocentesis. The procedure is done at 10 to 12 weeks and involves analyzing a sample of placental tissue. A thin tube inserted through the vagina and cervix is used to suction out the tissue sample. However, unlike amniocentesis, CVS cannot be used to test for neural tube defects, such as spina bifida and anencephaly. Therefore, it's usually recommended that a woman undergoing CVS also have the prenatal blood test called the maternal serum alpha fetoprotein (MSAFP) screening test, at about 16 to 18 weeks of pregnancy. This test identifies most (but not all) pregnancies at risk for neural tube defects.
If you have a choice of amniocentesis or CVS, discuss the risks and benefits of each and the possible results with your doctor and, if possible, a genetic counselor.
CVS is more attractive to some women because it can be done much earlier, at 10 weeks to 12 weeks. Many women say that this is a time when pregnancy is still a private issue. But other women feel the slightly higher risk of CVS is unacceptable, and they wait for the amniocentesis.
Amniocentesis and CVS are used to diagnose many, but not all, genetic disorders prenatally. If a genetic disorder for which a test is available has surfaced on either side of the family, or if you and your partner are carriers for the same testable recessive disorder, your health care professional will probably suggest testing, to determine if the fetus has inherited the disease. If two parents are carriers for the same recessive disorder, each child has a 25 percent chance of being born with the disease.
Of course, the ideal time for many tests is before you get pregnant. If you are planning a pregnancy, preconception genetic counseling sessions can help determine what, if any, conditions may be in your genetic background that future children could inherit. Preconception screening offers an opportunity to make decisions without the pressure of an advancing pregnancy. You can also start to take folic acid (4 mg/day) before conception to reduce your risk of having a baby with a neural tube defect.
Handling The Results
No test guarantees a healthy baby. While amniocentesis and CVS are extremely accurate, they look only for evidence of specific genetic or chromosomal disorders and cannot take into account other factors, including sporadic genetic mutations (without a hereditary component), which may affect a child's development.
When an untreatable genetic disorder is diagnosed prenatally, parents have the option of continuing or terminating the pregnancy. A genetic counselor can help you learn more about the disorder and weigh your options in a neutral setting. The decision is a tough one, and parents may weigh such factors as whether the disorder can be treated, the family's ability to manage the disorder or disability, the extent to which an affected child will be disabled or in pain, and how long the child is likely to live.
Prenatal testing can be valuable if you opt to continue a pregnancy knowing the child will be born with a particular disease. The diagnosis often can help you, your family and your health care team better manage the pregnancy, the delivery and any treatment the newborn will need.
In rare cases, a disorder diagnosed prenatally can be treated before birth. For example, congenital adrenal hyperplasia, which causes genital abnormalities in girls, can be treated with hormones given to the mother. Some centers are also experimenting with in utero surgery to correct spina bifida. But such opportunities to correct birth defects are still very much the exception.
Carrier Screening
You could be carrying a genetic mutation for a debilitating disease such as cystic fibrosis, sickle cell disease or Tay-Sachs disease and not even know it. That's because carriers of these mutations have no symptoms-in fact, they don't even have the disease.
Genes come in matched pairs, except for those on the sex chromosomes. In the case of autosomal recessive disorders such as these, if only one of these matched genes is damaged, there's no problem. The unaffected gene does the job. In fact, a disease-causing mutation can run through dozens of generations of a family without ever making itself known.
But if two carriers of the same gene change have a child, their chance of passing on what genetic counselors sometimes call a "double whammy"-two defective genes-is 25 percent. Of course, their chance of passing on two unaffected genes is also 25 percent, and the chance that a child will be a healthy carrier (with one normal gene and one defective one, but not afflicted with the disease) is 50 percent.
The exception to this pattern occurs if a disorder is recessive and X-linked. The X is the symbol for the larger sex chromosome. A child who inherits two X chromosomes is a girl. A child with an X chromosome and a Y chromosome is a boy. If a mother has a disease-linked recessive mutation on one of her X chromosomes, she is a carrier of the disorder but should have no or minimal symptoms herself. If she has a son, he will have a 50 percent risk of inheriting the disorder because he has no backup X chromosome; a daughter will have a 50 percent chance of being a carrier, like her mother.
Fragile X syndrome, as its name suggests, is one such X-linked disorder. Boys who inherit the mutation usually develop the disease, the most common form of genetically inherited mental retardation. Girls who inherit a fragile X mutation are more likely to be carriers. (The gene is unstable and the mutation tends to increase in size over succeeding generations, so that girls may eventually be affected as well, though the mental retardation is not usually as severe as it is in boys.) All affected individuals are related through females, as the fragile X gene "grows" only in the egg. If you have a family history of mental retardation, testing can determine whether a fragile X mutation is responsible and whether you are a carrier.
As with other types of testing, genetic counseling can help you understand carrier screenings. A counselor can also help you develop strategies for sharing the information with other family members who may also be at risk of carrying the mutation.
Carrier screening is recommended for any disorder that has surfaced in your family, either by virtue of a relative developing the disease or testing positive as a carrier. However, you should also consider screening for mutations found frequently in your particular ethnic group. The prevalence of genetic disorders is linked closely to ethnic heritage. Caucasians, for example, have a much higher risk than most other groups for cystic fibrosis, and those of African American descent are more likely to be carriers of sickle cell anemia mutations.
Many carrier screening tests are relatively inexpensive (usually $50 to $75 per individual screen) because they don't require sequencing of an entire gene. Instead they zero in on mutations known to be common in particular groups. The results are generally very accurate (95 percent or higher) and straightforward: A person is either a carrier or not.
Below is a list linking various groups to genetic disorders they are more likely to inherit:
-
Caucasians: phenylketonuria, hemochromatosis, cystic fibrosis, alpha 1-antitrypsin deficiency, celiac disease (no genetic test available, but physicians can test blood to measure levels of antibodies to gluten. These antibodies are antigliadin, anti-endomysium, and antireticulin.)
-
African Americans: sickle cell disease and thalassemia
-
East Asians (except Koreans): thalassemia
-
Irish, French Canadians and Cajuns: Tay-Sachs disease
-
Mediterraneans: thalassemia, celiac disease, and familial Mediterranean fever
-
Southeast Asians (Cambodians, Laotians and Vietnamese): hemoglobinopathies (disorders of hemoglobin, the oxygen-carrying component of red blood cells)
There is also a battery of tests for mutations found more often in the Ashkenazi Jewish population. The Ashkenazi are Jews of Central and East European descent, and they account for some 80 percent of the Jewish population in the United States.
The carrier screening tests for Ashkenazi Jews varies from program to program. Some test only for Tay-Sachs and Canavan diseases; some include many other disorders, such as Gaucher disease, Bloom syndrome, Fanconi anemia, Niemann-Pick disease and hereditary deafness. If you use insurance to pay for testing, you may have to use a particular center and test panel. Testing for Familial Dysautonomia is now available, too.
Many panels also include a screen for cystic fibrosis (CF). This condition is not more common in the Ashkenazi population. Caucasians are act | 
